JP2816227B2 - Anti-ulcer drug - Google Patents

Description

The present invention relates to an indole derivative represented by the following formulas (I) to (VII) and an addition salt thereof with a pharmacologically acceptable acid. The present invention relates to an anti-ulcer drug contained as an active ingredient.

(Prior art) Currently, drugs used as anti-ulcer drugs include gastric acid secretion inhibitors represented by cimetidine and many drugs having a gastrointestinal cell protective action, and these are symptoms of patients. It is used according to such as.

(Problems to be Solved by the Invention) However, many side effects have been reported for these known drugs. For example, cimetidine, which is widely used as a gastric acid secretion inhibitor, has a gynecomastia, Due to problems such as ulcer recurrence, improvement is desired.

The present inventors have conducted intensive studies based on these findings, and as a result, have found that the indole derivatives of the following formulas (I) to (VII) have a remarkable antiulcer effect, and have completed the present invention. .

(Means for Solving the Problem) That is, the present invention relates to compounds represented by formulas (I) to (VII) and An anti-ulcer drug comprising an indole derivative of the above as an active ingredient.

The compounds represented by the above formulas (I) to (VII) are known compounds per se. For example, the compound of the formula (I) is a chemical pharmacology bulletin (Chem. Pharm.
l.) 23 , 2805 (1975). However, its use as an anti-ulcer drug is not yet known. Similarly, the compound of formula (II) is a tetrahedron (Tetrahedron) 2
9 In 2015-2021 (1973), the compound of formula (III) is shown in Chemical Abstract (CA) 52 18485-d, and the compound of formula (IV) is shown in Journal of Organic Chemistry (JO
C.) 23 949 (1958) shows that the compound of formula (V) is a compound of Internacional Journal of New York Pharmacology.
tJNeuropharmacol.) 1967,6,423-429, and the compound of formula (VI) is described in Journal of Chemical Society, Chemical Communications (JCSChem.commun.) (1984).
In 847, the compound of formula (VII) is described in Pharmaceutical Journal 95 (10) 1152, respectively, but none of these compounds has any known use as an anti-ulcer drug.

According to the present invention, there is provided an anti-ulcer drug containing the indole derivative of the above formulas (I) to (VII) as an active ingredient.

It is shown in the test described later that the compounds represented by the above formulas (I) to (VII) of the present invention have a gastric acid secretion inhibitory action. Therefore, these compounds are expected to be used as antiulcer drugs.

According to the present invention, when the compounds represented by the formulas (I) to (VII) are used for pharmaceutical use, they can be formulated into various dosage forms. That is, the formulation can be administered orally in the form of tablets, dragees, hard capsules, soft capsules, solutions, emulsions or suspensions. In the case of parenteral administration, it is administered in the form of an injection solution.

In preparing these formulations, surrounding additives for formulation, such as excipients, stabilizers, preservatives, solubilizers,
Formulations can be made with the addition of wetting agents, emulsifiers, lubricants, sweeteners, coloring agents, flavoring agents, tonicity adjusters, buffers, antioxidants, and the like.

The dose of these compounds can vary over a wide range depending on the form of the preparation, the sex of the patient, and the degree of the disease. The daily dose of the active ingredient is preferably about 1 mg to 2 mg.
000 mg dose.

The cytotoxicity of these compounds (50% against KB cells)
The lethal concentration (IC ₅₀ value) is 6 to 25 μg / ml.

Next, the effect of the present invention as an anti-ulcer drug will be described.

Example H ⁺ / K ⁺ ATPase inhibitory activity It was measured as follows using H ⁺ / K ⁺ ATPase prepared from pig stomach.

H ⁺ / K ⁺ ATPase diluted solution 100μ (50μ as protein amount)
g) containing 4 mM magnesium chloride, 20 mM potassium chloride
Add 0 mM Pipes-Tris (pH 6.2) buffer 440μ,
Furthermore, a 5% ethanol solution of 0.1% nigericin
Was added. 5 μm of dimethyl sulfoxide was added thereto, and the mixture was incubated at 37 ° C. for 30 minutes. Then 4mM AT
10μm Pipes-Tris buffer 450μ containing disodium P
Was added to start the reaction, and after 30 minutes, the reaction was stopped by adding 0.1 ml of 50% trichloroacetic acid. The amount of free phosphoric acid generated in this reaction was determined by the method of D. Lebel, G. Poirier et al.
m.85,86~89,1978) by performing color measurement of 800nm by, was the reading of the absorbance at this time is C _1. Alternatively the absence of added potassium chloride be measured in the same manner, I was reading the absorbance at this and C _2.

Inhibition activity was measured in the above reaction by adding 5 μl of a dimethyl sulfoxide solution containing a 20 mg / ml inhibitor instead of dimethyl sulfoxide and performing the same operation, with or without potassium chloride. The absorbance readings were taken as T ₁ and T ₂ respectively.

The percent inhibition (I) of the inhibitor is calculated by the following formula:

I = [(C ₁ −C ₂ ) − (T ₁ −T ₂ )] × 100 / (C ₁ −C ₂ ) The compound represented by the formula (I) of the present invention can be used in various preparation forms in view of its pharmacological action. Specific preparation examples will be given below.

Formulation Example 1 Tablet (1 tablet) Compound of formula (I) 10 mg Lactose 67 mg Crystalline cellulose 15 mg Corn starch 7 mg Magnesium stearate 1 mg 100 mg Each component was uniformly mixed to obtain a powder for direct compression. This was formed into a tablet having a diameter of 6 mm and a weight of 100 mg by a rotary tableting machine.

Formulation Example 2 Granules (1 package) (Component A) Compound of formula (I) 10 mg Lactose 90 mg Corn starch 50 mg Crystalline cellulose 50 mg (Component B) Hydroxypropyl cellulose 10 mg Ethanol 90 mg After uniformly mixing Component A, Component B Was added and kneaded, sized by an extrusion granulation method, and then dried by a dryer at 50 ° C. Granules obtained by sieving the dried granules to a particle size of 297 μm to 1460 μm were obtained. The amount per package was 200 mg.

Formulation Example 3 Syrup preparation Compound of formula (I) 1.000 g Sucrose 30.000 g D-sorbitol 70 w / v% 25.000 g Ethyl parahydroxybenzoate 0.030 g Propyl parahydroxybenzoate 0.015 g Flavoring agent 0.200 g Glycerin 0.150 g 96% ethanol 0.500 g Distillation Water appropriate amount Total amount 100 ml Sucrose, D-sorbitol, ethyl paraoxybenzoate, propyl paraoxybenzoate and the above active ingredients were dissolved in 60 g of warm water. After cooling, a solution of flavor, dissolved in glycerin and ethanol, was added. Next, water was added to the mixture to make up to 100 ml.

Formulation Example 4 Injection solution Compound of formula (I) 2 mg CMC 2 mg distilled water 1 mg Distilled water was added to CMC and the active ingredient to prepare an injection solution.

(Effect of the Invention) The indole derivatives represented by the formulas (I) to (VII) show an excellent gastric acid secretion inhibitory effect as described above. Therefore, the present invention can provide an anti-ulcer drug.

──────────────────────────────────────────────────の Continued on front page (51) Int.Cl. ⁶ Identification code FI C07D 471/14 101 C07D 471/14 101 471/20 471/20 471/22 471/22 (58) Investigated field (Int.Cl. . ^6, DB name) C07D 209/14 C07D 401/06 C07D 471/14 C07D 471/20 C07D 471/22 CA, REGISTRY (STN)

Claims (1)

(57) [Claims] 1. The following formula: and An anti-ulcer drug comprising as an active ingredient at least one of an indole derivative represented by the formula (I) and an addition salt thereof with a pharmaceutically acceptable acid.